The proposed research will attempt to determine the role of decreased regional myocardiac blood flow and cell swelling in the development of decreased membrane integrity within ischemic hearts. Decreased membrane integrity will be correlated with (1) decreased cardiac specific activities of the cytoplasmic enzyme CPK and the lysosomal hydrolase cathepsin D and (2) direct light microscopic observation of frozen tissue sections. Furthermore, experiments will assess the ability of synthetic glucocorticoids, hypertonic solutions, or protease inhibitors to preserve the integrity of ischemic myocardial cells. Myocardial ischemia will be induced in anesthetized cats by ligation of the circumflex artery near its origin for one or two hours. The hemodynamic effects of the ligation will be assessed by continuous monitoring of the arterial blood pressure, left atrial pressure, and aortic blood flow. Regional myocardial blood flow will be determined prior to ligation and after one or two hours using radiolabeled microspheres. Lead II of the ECG will be recorded. Samples of arterial blood (6 ml) will be taken prior to occlusion and hourly thereafter for the determination of relative specific activities of creatine phosphokinase and the lysosomal hydrolase cathepsin D. One to two hours after ligation, the heart will be excised, divided into normal and ischemic left ventricular tissue and processed to determine: (a) regional myocardial blood flow, (b) myocardial activities of CPK and cathepsin D, (c) wet to dry weight ratios, and (d) prevalence of histologic indices of ischemic injury. Having established the degree of cellular disruption assciated with decreased myocardial blood flow or ischemic cell swelling, pharmacologic agents suggested to directly or indirectly stabilize cells membranes, i.e., glucocorticoids, hypertonic mannitol, or the protease inhibitor aprotinin, will be administered to cats subjected to circumflex artery ligation. Thus, it should be possible to determine the ability of these agents to limit myocardial cellular disruption within ischemic tissue and to relate the protective effect to a hemodynamic or membrane stabilizing action of these agents.